| 1 | Schizophr Bull 2012 May 38: 552-60 |
|---|---|
| PMID | 21041834 |
| Title | Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. |
| Abstract | Our genome-wide association study of schizophrenia found association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes in schizophrenia is gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability of schizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) in KALRN or EPHB1. The present study design consisted of 3 phases. At the discovery phase, we conducted resequencing analyses for all exon regions of KALRN and EPHB1 using a DNA microarray-based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320 schizophrenic patients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. In KALRN, we detected a significant association between schizophrenia and P2255T (OR = 2.09, corrected P = .048, 1 tailed); this was supported in the combined association analysis (OR = 2.07, corrected P = .006, 1 tailed). We found no evidence of association of EPHB1 with schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations. We provide evidence that multiple rare (<1%) missense mutations in KALRN may be genetic risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Schizophr Bull 2012 May 38: 552-60 |
| PMID | 21041834 |
| Title | Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. |
| Abstract | Our genome-wide association study of schizophrenia found association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes in schizophrenia is gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability of schizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) in KALRN or EPHB1. The present study design consisted of 3 phases. At the discovery phase, we conducted resequencing analyses for all exon regions of KALRN and EPHB1 using a DNA microarray-based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320 schizophrenic patients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. In KALRN, we detected a significant association between schizophrenia and P2255T (OR = 2.09, corrected P = .048, 1 tailed); this was supported in the combined association analysis (OR = 2.07, corrected P = .006, 1 tailed). We found no evidence of association of EPHB1 with schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations. We provide evidence that multiple rare (<1%) missense mutations in KALRN may be genetic risk factors for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Neurosci. 2015 Aug 35: 11266-80 |
| PMID | 26269635 |
| Title | Zic2 Controls the Migration of Specific Neuronal Populations in the Developing Forebrain. |
| Abstract | Human mutations in ZIC2 have been identified in patients with holoprosencephaly and schizophrenia. Similarly, Zic2 mutant mice exhibit holoprosencephaly in homozygosis and behavioral and morphological schizophrenic phenotypes associated with forebrain defects in heterozygosis. Despite the devastating effects of mutations in Zic2, the cellular and molecular mechanisms that provoke Zic2-deficiency phenotypes are yet unclear. Here, we report a novel role for this transcription factor in the migration of three different types of forebrain neurons: the Cajal-Retzius cells that populate the surface of the telencephalic vesicles, an amygdaloid group of cells originated in the caudal pole of the telencephalic pallium, and a cell population that travels from the prethalamic neuroepithelium to the ventral lateral geniculate nucleus. Our results also suggest that the receptor EPHB1, previously identified as a Zic2 target, may mediate, at least partially, Zic2-dependent migratory events. According to these results, we propose that deficiencies in cell motility and guidance contribute to most of the forebrain pathologies associated with Zic2 mutations. Although the phenotype of Zic2 mutant individuals was reported more than 10 years ago, until now, the main function of this transcription factor during early development has not been precisely defined. Here, we reveal a previously unknown role for Zic2 in the migration of forebrain neurons such as Cajal-Retzius cells, interneurons moving to the ventral lateral geniculate nucleus, and neocortical cells going to the amygdala. We believe that the role of this transcription factor in certain populations of migratory cells contributes to defects in cortical layering and hypocellularity in the ventral LGN and amygdala and will contribute to our understanding of the devastating phenotypes associated with Zic2 mutations in both humans and mice. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J. Neurosci. 2015 Aug 35: 11266-80 |
| PMID | 26269635 |
| Title | Zic2 Controls the Migration of Specific Neuronal Populations in the Developing Forebrain. |
| Abstract | Human mutations in ZIC2 have been identified in patients with holoprosencephaly and schizophrenia. Similarly, Zic2 mutant mice exhibit holoprosencephaly in homozygosis and behavioral and morphological schizophrenic phenotypes associated with forebrain defects in heterozygosis. Despite the devastating effects of mutations in Zic2, the cellular and molecular mechanisms that provoke Zic2-deficiency phenotypes are yet unclear. Here, we report a novel role for this transcription factor in the migration of three different types of forebrain neurons: the Cajal-Retzius cells that populate the surface of the telencephalic vesicles, an amygdaloid group of cells originated in the caudal pole of the telencephalic pallium, and a cell population that travels from the prethalamic neuroepithelium to the ventral lateral geniculate nucleus. Our results also suggest that the receptor EPHB1, previously identified as a Zic2 target, may mediate, at least partially, Zic2-dependent migratory events. According to these results, we propose that deficiencies in cell motility and guidance contribute to most of the forebrain pathologies associated with Zic2 mutations. Although the phenotype of Zic2 mutant individuals was reported more than 10 years ago, until now, the main function of this transcription factor during early development has not been precisely defined. Here, we reveal a previously unknown role for Zic2 in the migration of forebrain neurons such as Cajal-Retzius cells, interneurons moving to the ventral lateral geniculate nucleus, and neocortical cells going to the amygdala. We believe that the role of this transcription factor in certain populations of migratory cells contributes to defects in cortical layering and hypocellularity in the ventral LGN and amygdala and will contribute to our understanding of the devastating phenotypes associated with Zic2 mutations in both humans and mice. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Asia Pac Psychiatry 2016 Mar -1: -1 |
| PMID | 27028544 |
| Title | Association of EPHB1 rs11918092 and EFNB2 rs9520087 with psychopathological symptoms of schizophrenia in Chinese Zhuang and Han populations. |
| Abstract | Two single-nucleotide polymorphisms (SNPs) (rs11918092 and rs9520087) were genotyped in Chinese Zhuang and Han populations. Symptoms of schizophrenic patients were assessed by the Positive and Negative Syndrome Scale. No association of any SNP with schizophrenic susceptibility was found. However, associations of rs9520087 with the total scale score (P?=?0.014), positive scale score (P?=?0.013), negative scale score (P?=?0.032), and general psychopathology scale score (P?=?0.031) were found in Zhuang patients. Additionally, rs11918092 was associated with positive scale score (P?=?0.035) in Han patients. The two SNPs might influence symptoms of schizophrenia. © 2016 John Wiley & Sons Australia, Ltd. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Asia Pac Psychiatry 2016 Mar -1: -1 |
| PMID | 27028544 |
| Title | Association of EPHB1 rs11918092 and EFNB2 rs9520087 with psychopathological symptoms of schizophrenia in Chinese Zhuang and Han populations. |
| Abstract | Two single-nucleotide polymorphisms (SNPs) (rs11918092 and rs9520087) were genotyped in Chinese Zhuang and Han populations. Symptoms of schizophrenic patients were assessed by the Positive and Negative Syndrome Scale. No association of any SNP with schizophrenic susceptibility was found. However, associations of rs9520087 with the total scale score (P?=?0.014), positive scale score (P?=?0.013), negative scale score (P?=?0.032), and general psychopathology scale score (P?=?0.031) were found in Zhuang patients. Additionally, rs11918092 was associated with positive scale score (P?=?0.035) in Han patients. The two SNPs might influence symptoms of schizophrenia. © 2016 John Wiley & Sons Australia, Ltd. |
| SCZ Keywords | schizophrenia, schizophrenic |